N. J. Talley

Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosa, muscle layer, and subserosal tissues.

The aim of this study was to evaluate the clinicopathological spectrum of eosinophilic gastroenteritis and identify possible difficulties in establishing the diagnosis. All patients with a diagnosis of eosinophilic gastroenteritis, defined by the presence of gastrointestinal symptoms and eosinophilic infiltration of the gut (38), or a radiological diagnosis with peripheral eosinophilia (two), were identified from the Mayo Clinic records; in none was there evidence of extraintestinal disease. Patients were divided into three groups according to the Klein classification: predominant mucosal (23), muscular (12), or subserosal disease (five). A fourth group of patients (10) for comparison had abdominal symptoms and unexplained peripheral eosinophilia but no proven eosinophilic infiltration of the gut. It was found that a history of allergy was reported by 20 of 40 patients with eosinophilic gastroenteritis. Peripheral eosinophilia was absent in nine of 40. The patients with subserosal disease were distinct from the other groups in presentation (abdominal bloating, ascites), higher eosinophil counts and in their dramatic responses to steroid therapy. Otherwise the patients were similar regarding demographic factors, presenting symptoms (abdominal pain, nausea, weight loss, diarrhoea), and laboratory parameters. The ESR was moderately raised in 10 of 40 patients. The disease may affect any area of the gastrointestinal tract; eosinophilic infiltration was documented in the oesophagus in one patient and in the colon in two cases. Endoscopic biopsies missed the diagnosis in five of 40 presumably because of patchy disease. Eosinophilic gastroenteritis should be considered in the differential diagnosis of unexplained gastrointestinal symptoms even in the absence of peripheral eosinophilia.

GR 38032F (Ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man

The newly recognized class of 5-hydroxytryptamine receptors (5HT3) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT3 receptors are present on enteric neurons, and 5HT3 blockers may produce mild constipation; we thus hypothesized that 5HT3 receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT3 antagonist known to have antiemetic effects, influences colonic transit in health, a randomized, double-blind, placebo-controlled crossover study was performed. Using a radiopaque marker technique, colonic transit was quantified in 39 healthy volunteers (19 men, 20 nonpregnant women) 18–70 years of age. On a standard 25-g fiber diet, 16 mg of GR 38032F was given orally thrice daily. Gastrointestinal peptides (peptide YY, human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, substance P) were also measured in plasma fasting and postprandially. Mean total colonic transit time on placebo was 27.8 hr, while on GR 38032F it was 39.1 hr (P<0.0005). Transit times through the left colon (P<0.0005) and rectosigmoid (P<0.05) were prolonged by the drug, but right colonic transit was not significantly altered. Transit times did not correlate with age or gender, but subjects with shorter transit times were significantly more affected than were those with longer transit times. The peak release of peptide YY was minimally decreased following GR 38032F (P<0.01), but the peak and integrated postprandial responses of human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, and substance P were not significantly altered by the drug. We conclude that 5HT3 receptors may be involved in the regulation of colonic transit in healthy man.

Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5‐hydroxytryptamine type‐3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT3 antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea‐predominant irritable bowel syndrome were studied. A multilumen barostatmanometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function. We conclude that in diarrhoea‐predominant irritable bowel syndrome there is reduced rectal compliance and the rectum is abnormally sensitive to a pressure stimulus, but this is not altered by 5HT3‐blockade with ondansetron at the dose used.

A genetic association study of 5-HTT LPR and GNβ3 C825T polymorphisms with irritable bowel syndrome

Abstract  A pharmacogenetic study suggests the 5‐HTT LPR polymorphism predicts response to alosetron, and another study describes a possible association of the GNβ3 C825T polymorphism with IBS in patients with dyspepsia. We performed a case–control association study to determine whether these polymorphisms are associated with irritable bowel syndrome (IBS). The study aim was to compare allele and genotype frequencies between cases and controls for the 5‐HTT LPR and the GNβ3 C825T polymorphism. Cases were 50 GI outpatients; controls were 53 General Medicine outpatients matched to cases for age, gender and race at a major medical centre. Participants completed a questionnaire and donated blood. DNA was genotyped using polymerase chain reaction based assays. Eighty‐two per cent of cases met Rome II criteria for IBS: 12% constipation‐, 46% diarrhoea‐, and 42% mixed‐IBS. Genotype and allele frequencies for both polymorphisms did not differ between cases and controls. However, the allele frequency of the short (S) allele of the 5‐HTT LPR polymorphism was greater in those with mixed‐IBS compared with controls (68%vs 45%, P < 0.05). This study suggests that the 5‐HTT LPR polymorphism may be associated with mixed‐IBS, but not IBS overall. No association was observed for the GNβ3 C825T polymorphism with IBS overall or subtypes.

Methods for studying intestinal sensitivity and compliance: in vitro studies of balloons and a barostat

Abstract The aim of this study was to compare in vitro various methods for recording intestinal sensitivity and compliance. Relationships between volume and pressure were determined in segments of penrose tubing and pig gut (‘artificial intestine’) using pressure increments of 2 mmHg (0–24 mmHg). We tested two direct methods of distension of the entire segments (by syringe inflation and the Mayo barostat); we also used three different balloon devices for indirect distension (a 10 cm polyethylene barostat bag, a 10 cm latex condom balloon and a 6 cm latex condom balloon). Maximal distending diameters of the recording systems were measured by injecting from 0 to 160 mL of air. The elastic properties of the balloons were also tested by distensions in air and in rigid tubes. All recording systems accurately detected a lesser compliance of the penrose drain as compared to pig gut. In absolute terms, only the compliance measured with a polyethylene barostat bag distended with a syringe was not different from the compliance of the segment as measured directly. The bellows of our barostat and the latex balloons had significant intrinsic compliances which interfered with the recorded pressure‐volume curves. On the other hand, highly compliant plastic bags recorded most faithfully the compliance of artificial gut and that of non‐compliant rigid tubes. For comparable volumes of distension, external diameters were larger with the 6 cm latex balloon than with the 10 cm latex balloon or the 10 cm polyethylene barostat balloon. A polyethylene bag distended with a non‐compliant air injector (syringe) reflected most accurately the pressure‐volume relationships of tubular structures. The different maximal diameters assumed by the three distending devices may explain, in part, why lower volumes of distension are required to elicit symptoms with smaller distending balloons in vivo.

[14C]urea breath test for diagnosis of Helicobacter pylori

H. pylori is a potent urease producer, a characteristic that has been exploited in the development of the[14C]- and [13C]urea breath tests. The prevalence of H. pylori infection also is known to increase with advancing age; however, the individual patients age has not routinely been considered when interpreting urea breath test results. The aim of this study was to validate a short, age-adjusted [14C] urea breath test for use in diagnosing H. pylori infections. Forty-one subjects (28 volunteers, 13 patients) underwent esophagogastroduodenoscopy with biopsies. Subjects were defined as being H. pylori positive if histology or culture was positive. In addition, all subjects completed a 120-min [14C]urea breath test. A logistic regression analysis adjusting for age was used to estimate the probability of H. pylori positivity as a function of the14C values generated. Sixteen subjects were H. pylori-positive, and 25 were H. pylori negative. The14C values generated between 15 and 80 min were found to be equally predictive in identifying H. pylori-positive subjects. Advancing age was associated with a higher probability of H. pylori positivity. By taking advantage of the statistical probabilities, older patients could be accurately diagnosed with H. pylori at lower14C values. We found that [14C]urea breath test to be both a sensitive and specific test that can be abbreviated to a 30-min examination (total test time). Moreover, our mathematical model indicates that a patients age should be considered in order to optimize interpretation of the [14C]urea breath test, although further observations are needed to confirm this model.

Effect of selective 5HT3 antagonist (GR 38032F) on small intestinal transit and release of gastrointestinal peptides

Antagonists of 5-hydroxytryptamine type 3 (5HT3) receptors reduce the nausea induced by cisplatinum, but the effects of these agents on 5HT3 receptors in the human gut remain to be defined. We examined the actions of one of these drugs (Glaxo GR 38032F) on small intestinal transit and mouth-to-cecum transit times in healthy man. We also quantified its effects on the release of peptide YY (PYY), neurotensin, human pancreatic polypeptide, gastrin-cholecystokinin, and motilin. Ten healthy volunteers were enrolled in a randomized, double-blind, placebo-controlled crossover study. Following a single intravenous dose of GR 38032F (0.15 mg/kg), we measured the time to appearance in plasma of sulfapyridine after injection of salicylazosulfapyridine into the duodenum. This was used as a measure of duodenocecal transit. The appearance of hydrogen in breath after ingestion of a meal containing lactulose was also correspondingly used to quantify the mouth-to-cecum transit of the “head” of the meal. Gastrointestinal hormones were assayed in plasma by specific RIAs; samples were drawn fasting (10 min after injection) and after breakfast (358 calories: 15.7 g protein, 55.4 g carbohydrate, 8.1 g fat). The postprandial integrated response and peak release of PYY was decreased by GR 38032F. There was also a trend for the peak release of neurotensin to be reduced. GR 38032F did not significantly alter small intestinal transit times or mouth-to-cecum transit times. We conclude that GR 38032F does not have a major effect on small intestinal transit in health.

Non-ulcer dyspepsia: myths and realities.

Dyspepsia can be defined as the presence of upper abdominal pain or discomfort; other symptoms referable to the proximal gastrointestinal tract, such as nausea, early satiety, and bloating, may also be present. Symptoms may or may not be meal related. To be termed chronic, dyspepsia should have been present for three months or longer. Over half the patients who present with chronic dyspepsia have no evidence of peptic ulceration, other focal lesions, or systemic disease and are diagnosed as having non‐ulcer (or functional) dyspepsia. Non‐ulcer dyspepsia is a heterogeneous syndrome. It has been proposed that this entity can be subdivided into a number of symptomatic clusters or groupings that suggest possible underlying pathogenetic mechanisms. These groupings include ulcer‐like dyspepsia (typical symptoms of peptic ulcer are present), dysmotility (stasis)‐like dyspepsia (symptoms include nausea, early satiety, bloating, and belching that suggest gastric stasis or small intestinal dysmotility), and reflux‐like dyspepsia (heartburn or acid regurgitation accompanies upper abdominal pain or discomfort).

Prevalence ofHelicobacter pylori in specific forms of gastritis

Helicobacter pylori colonization of the gastric mucosa is strongly associated with chronic nonspecific gastritis; moreover, there is evidence to suggest thatH. pylori may cause this form of gastritis. However, there is little or no information on the prevalence ofH. pylori in specific forms of gastritis. Our hypothesis was that ifH. pylori was pathogenic in chronic nonspecific gastritis, organisms would be found frequently in this type of gastritis but infrequently in specific forms of gastritis. Prevalence rates ofH. pylori were determined independently in patients with eosinophilic and Crohns gastritis, Menetriers disease, and chronic nonspecific gastritis. The prevalence ofH. pylori in patients with chronic nonspecific gastritis was 71%, whereas the organism was not identified in patients with any form of specific gastritis. This finding further supports the accumulating evidence thatH. pylori is a primary pathogenic factor in chronic nonspecific gastritis.

Is Helicobacter pylori a Cause of Nonulcer Dyspepsia

The term “dyspepsia” means different things to different physicians. While no internationally accepted definition exits, one group of investigators defined dyspepsia to be upper abdominal or retrosternal pain, discomfort, heartburn, nausea, vomiting, or other symptom considered to be referrable to the proximal alimentary tract [8]. Although such a definition is probably too broad to be clinically useful, other groups have approached the problem in this way [2, 10, 22]. The majority of patients who present to physicians with chronic or recurrent dyspepsia, however it is defined, do not have a peptic ulcer or definite evidence of organic disease when investigated; such patients have been generally labelled as suffering from nonulcer dyspepsia (NUD) [48].